Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT61924T)

• DOT Name: DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3)
• Synonyms: DnaJ protein Tid-1; hTid-1; Hepatocellular carcinoma-associated antigen 57; Tumorous imaginal discs protein Tid56 homolog
• Gene Name: DNAJA3
• Related Disease:
  Congenital myasthenic syndrome
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal neoplasm
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Familial adenomatous polyposis
  Head-neck squamous cell carcinoma
  Metastatic malignant neoplasm
  Myocardial infarction
  Non-small-cell lung cancer
  Polyneuropathy
  Advanced cancer
  Complex neurodevelopmental disorder
  Glioma
  Neoplasm
  Schizophrenia
• UniProt ID: DNJA3_HUMAN
• PDB ID: 2CTT; 2DN9; 6IWS; 7X89
• Pfam ID: PF00226 ; PF01556 ; PF00684
• Sequence:
  MAARCSTRWLLVVVGTPRLPAISGRGARPPREGVVGAWLSRKLSVPAFASSLTSCGPRAL
  LTLRPGVSLTGTKHNPFICTASFHTSAPLAKEDYYQILGVPRNASQKEIKKAYYQLAKKY
  HPDTNKDDPKAKEKFSQLAEAYEVLSDEVKRKQYDAYGSAGFDPGASGSQHSYWKGGPTV
  DPEELFRKIFGEFSSSSFGDFQTVFDQPQEYFMELTFNQAAKGVNKEFTVNIMDTCERCN
  GKGNEPGTKVQHCHYCGGSGMETINTGPFVMRSTCRRCGGRGSIIISPCVVCRGAGQAKQ
  KKRVMIPVPAGVEDGQTVRMPVGKREIFITFRVQKSPVFRRDGADIHSDLFISIAQALLG
  GTARAQGLYETINVTIPPGTQTDQKIRMGGKGIPRINSYGYGDHYIHIKIRVPKRLTSRQ
  QSLILSYAEDETDVEGTVNGVTLTSSGGSTMDSSAGSKARREAGEDEEGFLSKLKKMFTS
• Function: Modulates apoptotic signal transduction or effector structures within the mitochondrial matrix. Affect cytochrome C release from the mitochondria and caspase 3 activation, but not caspase 8 activation. Isoform 1 increases apoptosis triggered by both TNF and the DNA-damaging agent mytomycin C; in sharp contrast, isoform 2 suppresses apoptosis. Can modulate IFN-gamma-mediated transcriptional activity. Isoform 2 may play a role in neuromuscular junction development as an effector of the MUSK signaling pathway.
• Tissue Specificity: Widely expressed with highest levels in heart, liver, lung and skeletal muscles. Also expressed in keratinocytes.
• KEGG Pathway: Viral carcinogenesis (hsa05203)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myasthenic syndrome	DISJLG2T	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[4]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[4]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[5]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[6]
Familial adenomatous polyposis	DISW53RE	Strong	Genetic Variation	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[7]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[3]
Myocardial infarction	DIS655KI	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Polyneuropathy	DISB9G3W	Strong	Biomarker	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[7]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal recessive	[10]
Glioma	DIS5RPEH	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Biomarker	[7]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[12]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[19]
Marinol	DM70IK5	Approved	Marinol decreases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[20]
Selenium	DM25CGV	Approved	Selenium decreases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[22]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[19]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[25]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of DnaJ homolog subfamily A member 3, mitochondrial (DNAJA3).	[27]

References

• [1] Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. Hum Mol Genet. 2010 Jun 15;19(12):2370-9. doi: 10.1093/hmg/ddq110. Epub 2010 Apr 6.
• [2] Beta-Amyloid Increases the Expression Levels of Tid1 Responsible for Neuronal Cell Death and Amyloid Beta Production.Mol Neurobiol. 2020 Feb;57(2):1099-1114. doi: 10.1007/s12035-019-01807-2. Epub 2019 Nov 4.
• [3] Tid1 negatively regulates the migratory potential of cancer cells by inhibiting the production of interleukin-8.Cancer Res. 2005 Oct 1;65(19):8784-91. doi: 10.1158/0008-5472.CAN-04-4422.
• [4] Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor.Int J Mol Med. 2008 Jan;21(1):19-31.
• [5] A crucial role of mitochondrial Hsp40 in preventing dilated cardiomyopathy.Nat Med. 2006 Jan;12(1):128-32. doi: 10.1038/nm1327. Epub 2005 Dec 4.
• [6] Tumorous imaginal disc 1 (TID1) inhibits isoproterenol-induced cardiac hypertrophy and apoptosis by regulating c-terminus of hsc70-interacting protein (CHIP) mediated degradation of Gs.Int J Med Sci. 2018 Oct 20;15(13):1537-1546. doi: 10.7150/ijms.24296. eCollection 2018.
• [7] HSP40 co-chaperone protein Tid1 suppresses metastasis of head and neck cancer by inhibiting Galectin-7-TCF3-MMP9 axis signaling.Theranostics. 2018 Jun 13;8(14):3841-3855. doi: 10.7150/thno.25784. eCollection 2018.
• [8] Tid1-S regulates the mitochondrial localization of EGFR in non-small cell lung carcinoma.Oncogenesis. 2017 Jul 17;6(7):e361. doi: 10.1038/oncsis.2017.62.
• [9] A novel variant of the human mitochondrial DnaJ protein, Tid1, associates with a human disease exhibiting developmental delay and polyneuropathy.Eur J Hum Genet. 2019 Jul;27(7):1072-1080. doi: 10.1038/s41431-019-0358-9. Epub 2019 Feb 15.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] Identification of a hTid-1 mutation which sensitizes gliomas to apoptosis.FEBS Lett. 2004 Dec 17;578(3):323-30. doi: 10.1016/j.febslet.2004.11.034.
• [12] Genome-wide association study of schizophrenia in Ashkenazi Jews.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.
• [13] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [14] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [18] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [19] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [23] Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 2017 Nov;32(11):2400-2413. doi: 10.1002/tox.22453. Epub 2017 Aug 10.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [26] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [27] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.